Version May 2024
INTRODUCTION — The designations "group C Streptococcus" (GCS) and "group G Streptococcus" (GGS) are used by clinical microbiology laboratories to denote clinical isolates of streptococci that react with Lancefield group C or G typing serum and, like Streptococcus pyogenes (group A Streptococcus), form large colonies on sheep blood agar, typically surrounded by a zone of beta-hemolysis (picture 1 and algorithm 1).
GCS and GGS are normal commensal flora of the human upper airway and frequently are asymptomatic colonizers of the skin, gastrointestinal tract, and female genital tract. They are also implicated in mono- and polymicrobial infections of the skin and soft tissues, pharyngitis, bacteremia and endocarditis, septic arthritis and osteomyelitis, puerperal infections, and meningitis.
GCS and GGS of human origin are now considered to constitute a single subspecies, Streptococcus dysgalactiae subsp equisimilis (SDSE). A comparison of the complete genome sequence of a clinical isolate of GGS S. dysgalactiae subsp equisimilis with that of other streptococcal species demonstrated it is most closely related to S. pyogenes, with 72 percent sequence similarity [1]. SDSE shares many virulence determinants with S. pyogenes, including the antiphagocytic M protein, streptolysin O, streptolysin S, streptokinase, and one or more pyrogenic exotoxins similar to those implicated in streptococcal toxic shock [1-3].
GCS and GGS of animal origin are occasionally associated with human infection; these bacteria belong to distinct species. (See 'Microbiology' below.)
Streptococci in the S. anginosus or S. milleri group may also react with C or G typing sera, but these organisms are distinguished by the fact that they form small (<0.5 mm) colonies on sheep blood agar. They are normally identified by diagnostic laboratories as belonging to the S. anginosus or S. milleri group, not as GCS or GGS. (See "Infections due to the Streptococcus anginosus (Streptococcus milleri) group".)
MICROBIOLOGY — A precise definition of the bacterial species encompassed by Lancefield serologic groups C and G has been elusive for two reasons. First, no single streptococcal species is uniquely identifiable via the expression of group C or group G antigen; this is in contrast with, for example, group B Streptococcus, which corresponds to a single species, Streptococcus agalactiae. Second, the taxonomy of the organisms identified as belonging to group C or G has been inconsistent and has evolved over time.
Beginning in the 1930s, the designation Streptococcus equisimilis was used for beta-hemolytic streptococci of human origin belonging to Lancefield group C. The designation S. dysgalactiae was used for alpha-hemolytic streptococci isolated from cows belonging to Lancefield group C. DNA homology studies in the 1980s indicated that both of these streptococci, in addition to large-colony streptococci of group G and L, belonged to a single species, S. dysgalactiae.
In 1996, it was proposed that the species be subdivided into two subspecies [4]:
●S. dysgalactiae subsp equisimilis (SDSE) corresponding to large-colony beta-hemolytic human isolates expressing Lancefield group C or G antigen
●S. dysgalactiae subsp dysgalactiae corresponding to large-colony variably hemolytic animal isolates expressing Lancefield group C or L antigen [4]
The vast majority of clinical isolates associated with human infection that are identified as group C or G streptococci belong to the former taxon, SDSE [5]. Rarely, clinical isolates of SDSE express the Lancefield group A antigen instead of group C or G as a result of genetic recombination between highly similar gene clusters. These clusters encode proteins that direct synthesis of the group-specific carbohydrate antigen of group A (S. pyogenes) and that of group C or G (SDSE) streptococci [6].
Various streptococci of animal origin also express the group C or G antigen and are occasionally implicated in human infection. Among GCS, Streptococcus equi subsp equi and S. equi subsp zooepidemicus are associated primarily with horses, in which they cause, respectively, suppurative lymphadenitis (strangles) and respiratory infections [7]. The GGS, S. canis, is associated with several animal species, including dogs, cats, and cattle [5,8].
EPIDEMIOLOGY — Because GCS and GGS represent normal human flora, infections due to these bacteria are not restricted by geographic locale or particular social or occupational activities. Several clinical case series have found GCS and GGS infections to be more common among older adults and in individuals with underlying chronic illness. The burden of invasive disease due to GCS and GGS is similar to that attributable to group A Streptococcus (S. pyogenes) [9]. A population-based surveillance in British Columbia, Canada, from 2011 to 2018, identified 210 episodes of bloodstream infection due to beta-hemolytic streptococci [10]. The incidence of group C/G bloodstream infection was 5.5 per 100,000 population compared with 4.2 and 4.7 per 100,000 for groups A and B streptococci, respectively.
The incidence of invasive disease may be increasing: a retrospective review of bacteremia from two centers in Canada between 2007 and 2014 noted an increase in the proportion of bacteremias due to GCS (4 to 6 percent) and GGS (0.4 to 1.5 percent) [11]. Another study reported the incidence of invasive infection due to GCS and GGS in western Norway increased between 1999 and 2013 from 1.4 per 100,000 to 6.3 per 100,000, and the authors suggested that the increase was due to aging of the overall population [12]. Genomic analysis of invasive isolates from both regions revealed that a limited number of clonal groups are responsible for the majority of cases, a finding that suggests emergence of a few particularly virulent clones of S. dysgalactiae subsp equisimilis may account for the increasing prevalence of bacteremia and other invasive disease syndromes [13,14].
Zoonotic infections with S. equi subsp zooepidemicus have been reported occasionally in individuals with exposure to farm animals, especially horses, although not all human infections with this organism can be linked to animal contact [15,16]. Several well-documented outbreaks of infection with S. equi subsp zooepidemicus have been attributed to ingestion of inadequately pasteurized dairy products, in some cases complicated by poststreptococcal glomerulonephritis [17-20]. Rare cases of human infection with S. canis have been associated with household contact with dogs [21-23].
CLINICAL MANIFESTATIONS — GCS and GGS have been implicated in a wide variety of human infections: pharyngitis, a range of skin and soft tissue infections (including impetigo, infected ulcers, wound infections, cellulitis, and necrotizing soft tissue infection), bacteremia, endocarditis, septic arthritis, osteomyelitis, pleuropulmonary infections, peritonitis, intra-abdominal abscess, meningitis, puerperal sepsis, neonatal sepsis, and streptococcal toxic shock-like syndrome [24-27].
While poststreptococcal glomerulonephritis has been reported as a sequel of infection with the animal-associated GCS S. equi subsp zooepidemicus, neither GCS nor GGS has been shown to trigger acute rheumatic fever. (See 'Epidemiology' above.)
Bacteremia — In the population-based survey from British Columbia, GCS and GGS together accounted for 38 percent of beta-hemolytic streptococcal bacteremias [10]. Community-associated infections made up 58 percent and 41 percent were health care associated. The median age was 68 years and 68 percent of patients were male. Associated focal infections involved soft tissues (56 percent), bone and joint (10 percent), abdominal/pelvic (5 percent), or cardiovascular sites (4 percent).
Clinical syndromes associated with GCS bacteremia include endocarditis, meningitis, cutaneous infection, intra-abdominal infection, pneumonia, sinusitis, pharyngitis, epiglottitis, arthritis, osteomyelitis, mycotic aneurysm, fistula infection, genitourinary tract infection, and pericarditis. Mortality is approximately 15 percent [10,28,29].
Case series exclusive to GGS bacteremia have described similar clinical features: advanced age, malignancy, diabetes, and alcohol use as underlying conditions; the skin as the most common source; and endocarditis and bone and joint infections as associated clinical syndromes [30-38].
Endocarditis — In some series of patients with invasive GCS or GGS infection, bacteremia has been associated with endocarditis in 25 to 50 percent of cases [28,32,39,40]. Endocarditis has been reported both in patients with preexisting valvular disease and in patients with previously normal valves. Embolic complications are common and may be associated with large valvular vegetations. Some authors favor consideration of early valve replacement because of the risk of embolic events, especially stroke [41].
Arthritis — Septic arthritis is a relatively frequent presentation of invasive GCS or GGS infection, with or without detectable bacteremia [42-46]. Patients are frequently older adults with underlying chronic illness, and there appears to be a male predominance. Preexisting arthritis and the presence of a prosthetic joint are common predisposing factors. The knee is involved most often; polyarticular infection occurs occasionally and should suggest the possibility of concomitant endocarditis.
Skin and soft tissue infections — GCS and GGS have been implicated as a cause of skin and soft tissue infection, particularly in the setting of preexisting vascular or lymphatic compromise. Recurrent lower extremity cellulitis has been described after saphenous venectomy for coronary artery bypass surgery, sometimes in association with tinea pedis and colonization of the web space between the toes [47,48]. Anal colonization may also be a source for recurrent infection [49]. Recurrent GGS bacteremia occurred in 14 percent of patients in one series and was frequently associated with underlying lymphatic disorders [36]. Necrotizing fasciitis similar to that caused by S. pyogenes has also been observed, in some cases associated with streptococcal toxic shock-like syndrome [25,50,51].
Pharyngitis — Epidemic pharyngitis has been reported from foodborne infection with GCS or GGS, particularly in semiclosed populations such as military installations or schools [18,52,53]. Dairy products, egg salad, and chicken salad have been implicated as sources.
Respiratory outbreaks of GGS pharyngitis via person-to-person transmission have also been described [54]. In contrast, the role of GCS and GGS in sporadic or endemic pharyngitis is controversial. Some studies have found higher isolation rates of GCS or GGS in throat cultures of individuals with symptomatic pharyngitis compared with asymptomatic controls, whereas others have not [55-58].
One retrospective study in a large community-based health system evaluated results of 116,578 throat cultures in children from 0 to 18 years of age. Non-group A beta-hemolytic streptococci were recovered in 3.1 percent of encounters, compared with group A streptococci (GAS or S. pyogenes) identified in 22.8 percent. While the non-group A streptococci (NGAS) were not further characterized, they were presumed to represent predominantly GCS or GGS. Patients with NGAS had significantly lower rates of fever, throat erythema, and lymphadenopathy and higher rates of cough and rhinorrhea compared with those with GAS. These findings suggested that a higher proportion of NGAS patients were carriers with viral pharyngitis compared to the GAS group [59].
Thus, with the possible exception of a suspected outbreak, the isolation of GCS or GGS in a throat culture from a patient with pharyngitis is of uncertain significance. GCS and GGS are not detected by rapid antigen tests for GAS pharyngitis because they lack the group A antigen that is the target of these tests.
DIAGNOSTIC EVALUATION — Diagnosis of infection due to GCS and GGS depends on identification of the organism in a culture from a clinical specimen. In general, a positive culture from a normally sterile site, such as blood, synovial fluid, or cerebrospinal fluid (CSF), can be considered definitive evidence of infection in the setting of a compatible clinical syndrome. The interpretation of positive cultures for GCS or GGS from the pharynx or from cutaneous sites such as open ulcers or wounds is less straightforward since asymptomatic colonization of the upper airway and skin also occurs.
Microbiologic identification of large-colony beta-hemolytic streptococci as GCS or GGS may be done by Lancefield serologic grouping. The use of bacitracin sensitivity as a screening method to identify S. pyogenes may falsely identify GCS or GGS as S. pyogenes, since 15 percent of S. dysgalactiae subsp equisimilis isolates were susceptible to bacitracin in one study [5].
Identification to the species or subspecies level is not routinely done in many clinical diagnostic laboratories but can be accomplished by a series of individual biochemical tests or commercially available biochemical test panels or by 16S and 23S ribosomal RNA gene sequencing [24,60]. Helpful biochemical tests to distinguish GCS and GGS from other beta-hemolytic streptococci include a negative pyrrolidonyl arylamidase test (S. pyogenes is positive), negative hippurate test (S. agalactiae is positive), positive beta-D-glucuronidase test (S. anginosus group is negative), and negative Voges-Proskauer test (S. anginosus group is positive).
Isolates belonging to the S. anginosus or S. milleri group may express the Lancefield group C or G (or A or F) antigen but can be distinguished from large-colony GCS and GGS by their smaller colony size (<0.5 mm), a negative beta-D-glucuronidase test, and a positive Voges-Proskauer test.
TREATMENT — GCS and GGS are susceptible to beta-lactam antibiotics.
Penicillin is considered the drug of choice for treatment of GCS and GGS infections [24,61,62]:
●Treatment of GCS or GGS cellulitis consists of penicillin G 2 million units intravenously (IV) every 4 to 6 hours (for children: 50,000 units/kg/dose, not to exceed adult dose).
●Treatment of bacteremia, severe invasive soft tissue infection, endocarditis, osteomyelitis, or septic arthritis due to GCS or GGS consists of penicillin G 4 million units IV every 4 hours (for children: 75,000 units/kg/dose, not to exceed adult dose).
Third-generation cephalosporins are also highly active and are suitable alternative agents. Options include cefotaxime 2 g IV every 6 hours (for children: 50 mg/kg/dose IV every 6 hours, not to exceed adult dose) or ceftriaxone 2 g IV every 24 hours (for children: 50 mg/kg/dose IV every 24 hours, not to exceed adult dose).
The duration of treatment should be tailored to clinical response and generally should be continued until at least three days after resolution of fever and other clinical signs. General guidelines are 7 to 10 days for cellulitis, 14 days for bacteremia, 14 to 28 days for severe invasive soft tissue infection, 28 to 42 days for osteomyelitis or septic arthritis, and 28 to 42 days for endocarditis.
Issues related to treatment of specific infections are discussed further separately. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Necrotizing soft tissue infections".)
For patients with a history of severe hypersensitivity reactions to beta-lactam antibiotics, vancomycin may be used. Linezolid and daptomycin are active in vitro, but clinical experience in treating GCS and GGS infections with either agent is limited. The prevalence of resistance to macrolides is highly variable but has been as high as 15 to 25 percent in some areas and is sometimes associated with inducible clindamycin resistance [62-64]. High-level resistance to fluoroquinolones has been described in a small percentage of clinical isolates [61,65].
Treatment of pharyngitis when GCS or GGS has been isolated from a throat culture may be indicated in the setting of a point-source (eg, foodborne) outbreak or in sporadic cases in which clinical features suggest pyogenic bacterial infection (ie, fever, tonsillar exudates, tender cervical lymphadenopathy, and absence of cough or rhinorrhea) [66]. The same regimens recommended for S. pyogenes are suitable for GCS/GGS pharyngitis. However, GCS/GGS pharyngitis is not known to trigger acute rheumatic fever; therefore, a treatment course of 5 days (rather than 10 days) is reasonable. (See "Treatment and prevention of streptococcal pharyngitis in adults and children".)
SUMMARY
●Microbiology – Large-colony beta-hemolytic streptococci that express the Lancefield group C or G antigen are normal flora of the human respiratory, gastrointestinal, and female genital tracts. All group C or G streptococci belong to a single subspecies, Streptococcus dysgalactiae subsp equisimilis. (See 'Introduction' above.)
Streptococci in the S. anginosus or S. milleri group may also react with C or G typing sera, but they are not categorized as group C or G streptococci. (See 'Introduction' above.)
●Epidemiology – Because group C and G streptococci represent normal human flora, infections due to these bacteria are not restricted by geographic locale or particular social or occupational activities. Several clinical case series have found infections from these organisms to be more common among older adults and in individuals with underlying chronic illness. (See 'Epidemiology' above.)
●Clinical manifestations – Syndromes associated with these organisms include bacteremia, endocarditis, septic arthritis, skin and soft tissue infections, and epidemic pharyngitis as well as a variety of other less common infection syndromes. (See 'Clinical manifestations' above.)
●Antimicrobial therapy – Group C and G streptococci are universally susceptible to beta-lactam antibiotics, and penicillin is the treatment of choice for serious infection. (See 'Treatment' above.)
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